NT-702, a Selective Phosphodiesterase 3 Inhibitor, Dilates Rabbit Spinal Arterioles via Endothelium-Dependent and Endothelium-Independent Mechanisms

Abstract

Abstract:We investigated the effects of NT-702, a selective phosphodiesterase (PDE) 3 inhibitor, on arterioles isolated from rabbit lumbar spinal cords. NT-702 caused a dose-dependent dilation of the isolated spinal arterioles. The disruption of endothelium produced a significant reduction of higher concentrations (10 -7 and 10 -6 M ), but not lower concentrations (less than 10 -8 M ), of NT-702-induced vasodilation. The NT-702-induced vasodilation of the arterioles with endothelium was not affected by pretreatment with an inhibitor of nitric oxide, cyclooxygenase, or cytochrome P-450 monooxygenase. In contrast, catalase reduced significantly the higher concentrations of NT-702-induced vasodilation only. Tetraethylammonium (TEA) completely reduced the lower concentrations of NT-702-induced vasodilation, but decreased only partially the higher concentrations of NT-702-induced vasodilation of the arterioles with endothelium. Hydrogen peroxide dilated significantly the isolated arterioles with endothelium, the response of which was reduced significantly by TEA. KT5720 (a selective protein kinase inhibitor) significantly decreased both the lower and higher concentrations of NT-702-induced vasodilation of the arterioles with endothelium. The findings suggest that NT-702 dose-dependently dilated the isolated spinal arterioles of rabbits via endotheliumdependent and endothelium-independent mechanisms. Protein kinase A (PKA)-and TEA-sensitive K + channels may be involved in the NT-702-induced vasodilation. Moreover, hydrogen peroxide may contribute in part to the endothelium-dependent higher concentrations of NT-702-induced vasodilation.